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*The last efficacy trial conducted to date is the HVTN 505 trial, a randomized, placebo-controlled trial of a prime boost, DNA/rAd5 vaccine consisting of a 6-plasmid DNA vaccine. <ref name="pmid24099601">{{cite journal |vauthors=Hammer SM, Sobieszczyk ME, Janes H, Karuna ST, Mulligan MJ, Grove D, Koblin BA, Buchbinder SP, Keefer MC, Tomaras GD, Frahm N, Hural J, Anude C, Graham BS, Enama ME, Adams E, DeJesus E, Novak RM, Frank I, Bentley C, Ramirez S, Fu R, Koup RA, Mascola JR, Nabel GJ, Montefiori DC, Kublin J, McElrath MJ, Corey L, Gilbert PB |title=Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine |journal=N. Engl. J. Med. |volume=369 |issue=22 |pages=2083–92 |date=November 2013 |pmid=24099601 |pmc=4030634 |doi=10.1056/NEJMoa1310566 |url=}}</ref> | *The last efficacy trial conducted to date is the HVTN 505 trial, a randomized, placebo-controlled trial of a prime boost, DNA/rAd5 vaccine consisting of a 6-plasmid DNA vaccine. <ref name="pmid24099601">{{cite journal |vauthors=Hammer SM, Sobieszczyk ME, Janes H, Karuna ST, Mulligan MJ, Grove D, Koblin BA, Buchbinder SP, Keefer MC, Tomaras GD, Frahm N, Hural J, Anude C, Graham BS, Enama ME, Adams E, DeJesus E, Novak RM, Frank I, Bentley C, Ramirez S, Fu R, Koup RA, Mascola JR, Nabel GJ, Montefiori DC, Kublin J, McElrath MJ, Corey L, Gilbert PB |title=Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine |journal=N. Engl. J. Med. |volume=369 |issue=22 |pages=2083–92 |date=November 2013 |pmid=24099601 |pmc=4030634 |doi=10.1056/NEJMoa1310566 |url=}}</ref> | ||
* The vaccine induced both cellular and humoral responses. However, these were not associated with protection.<ref name="pmid24099601">{{cite journal |vauthors=Hammer SM, Sobieszczyk ME, Janes H, Karuna ST, Mulligan MJ, Grove D, Koblin BA, Buchbinder SP, Keefer MC, Tomaras GD, Frahm N, Hural J, Anude C, Graham BS, Enama ME, Adams E, DeJesus E, Novak RM, Frank I, Bentley C, Ramirez S, Fu R, Koup RA, Mascola JR, Nabel GJ, Montefiori DC, Kublin J, McElrath MJ, Corey L, Gilbert PB |title=Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine |journal=N. Engl. J. Med. |volume=369 |issue=22 |pages=2083–92 |date=November 2013 |pmid=24099601 |pmc=4030634 |doi=10.1056/NEJMoa1310566 |url=}}</ref> | * The vaccine induced both cellular and humoral responses. However, these were not associated with protection.<ref name="pmid24099601">{{cite journal |vauthors=Hammer SM, Sobieszczyk ME, Janes H, Karuna ST, Mulligan MJ, Grove D, Koblin BA, Buchbinder SP, Keefer MC, Tomaras GD, Frahm N, Hural J, Anude C, Graham BS, Enama ME, Adams E, DeJesus E, Novak RM, Frank I, Bentley C, Ramirez S, Fu R, Koup RA, Mascola JR, Nabel GJ, Montefiori DC, Kublin J, McElrath MJ, Corey L, Gilbert PB |title=Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine |journal=N. Engl. J. Med. |volume=369 |issue=22 |pages=2083–92 |date=November 2013 |pmid=24099601 |pmc=4030634 |doi=10.1056/NEJMoa1310566 |url=}}</ref> | ||
None of the vaccine candidates that have completed efficacy trials to date induced strong bnAb responses. CD8+ T cell responses were induced in STEP, Phambili and HVTN505 studies but were not associated with protection. Only one trial, RV144 demonstrated efficacy and protection was associated with functional binding antibodies. However, efficacy was of suboptimal magnitude and was not durable. | |||
==HIV Vaccine== | ==HIV Vaccine== | ||
Revision as of 21:33, 6 December 2018
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Marjan Khan M.B.B.S.[2]
Overview
HIV infection is a major global health issue, affecting 36.7 million people world-wide. The number of people living with HIV on antiretroviral therapy (ART) reached 17 million in 2015. Although ART has dramatically reduced morbidity and mortality in individuals with HIV infection and can also prevent HIV transmission but it cannot eradicate HIV infection due to the persistence of a latent viral reservoir, hence the need for ART is lifelong and the cost is substantial. Although ART is highly efficacious in preventing transmission in the setting of mother to child transmission, in sexual transmission through the treatment of infected partners in relationships, through pre-exposure or or post-exposure prophylaxis, but all these scale-up difficulties and costs may make widespread implementation challenging.Thus an HIV vaccine is essential as it is a more sustainable solution.The development of a universal effective HIV vaccine is an exceptionally difficult biomedical challenge. Firstly, no case of natural eradication of HIV infection has been identified, thus mechanisms of protection have not been definitively established. Secondly, the extreme diversity of HIV is a major obstacle as strains belonging to different subtypes can differ by up to 35% in their envelope (Env) proteins.Thus, vaccine immunogens derived from a particular strain may not be effective against other strain. To generate an efficacious global vaccine, immunogens capable of generating protective responses covering most major strains are required.
Historical Perspective
- Ever since HIV was formally identified as the cause of AIDS, there have been ongoing efforts on vaccines against the disease.
- On April 24, 1984, the US Secretary of Health and Human Services, Margaret Heckler, announced that vaccines will be researched and made ready for preliminary testing by the year 1986. [1]
- Traditional approaches of using live attenuated or whole inactivated viruses were considered unsafe because of the risk of permanently integrating proviral DNA within host chromosomes.[2]
- Advancements in vaccine development had to wait until mid-1980s when recombinant DNA technologies were becoming available for research applications. Following the success of recombinant Hepatitis B vaccine, recombinant DNA technologies were also being researched for HIV vaccines. [3]
- All these efforts came to a standstill with growing knowledge about extreme mutability and immune evasion mechanisms of existing HIV strains. [4]
- It was further complicated by the fact that neutralizing antibodies had no protective effects and their titers were similar among asymptomatic carriers and patients with active disease. [5]
- The 6 HIV-1 vaccine efficacy trials done to date, to delineate potential protective responses, and to explore new vaccine candidates that are currently being developed are as follows.
VAX003 and 004
- VAX003 was a double-blind, randomized trial of AIDSVAX® B/E (a bivalent vaccine composed of rgp120 from subtype B, strain MN and subtype CRF01_AE, strain A244) in injection drug users (IDU) in Thailand.[6]
- VAX004 was a double-blind, randomized trial of AIDSVAX® B/B (a bivalent vaccine composed of subtype B rgp120 from strains MN and GNE8) conducted among men who have sex with men (MSM) and women at high risk for heterosexual transmission of HIV-1 in North America and The Netherlands.[7]
- Despite the development of anti-gp120 antibody responses, both vaccines did not demonstrate protection.
- The disappointing results from the VAX003 and VAX004 trials and data supporting the importance of cell mediated immunity in controlling viral replication in rhesus macaques and human elite controllers,attention turned to the use of T-cell vaccines to induce HIV-specific cellular immune responses.[8] [9] [10]
STEP and phambili studies
- The STEP study was a double-blind, randomized trial of the MRKAd5 HIV-1 gag/pol/nef sub-type B vaccine in individuals at high risk of HIV-1 acquisition in the Americas, Caribbean and Australia. [11]
- The Phambili study was a double-blind, randomized trial designed to evaluate the MRKAd5 HIV-1 gag/pol/nef sub-type B vaccine in individuals in South Africa where HIV clade C is predominant. This study was halted following the Step study's interim analysis and subsequent analysis also found no efficacy.[12]
RV144
- It was a randomized, double-blind trial that evaluated 4 priming injections of ALVAC-HIV [vCP1521], recombinant canarypox vector expressing HIV-1 Gag and Pro (subtype B LAI strain) and CRF01_AE (subtype E) HIV-1 gp120 (92TH023) linked to the transmembrane anchoring portion of gp41 (LAI) plus 2 booster injections, AIDSVAX® B/E (bivalent HIV-1 gp120 subunit vaccine containing a subtype E Env from strain A244 (CM244) and a subtype B Env from strain MN), co-formulated with alum.[13]
- The rationale for the prime boost strategy was to induce both cellular and humoral responses.
- The RV144 trial was the only efficacy trial to date that demonstrated efficacy.[14]
HVTN 505
- The last efficacy trial conducted to date is the HVTN 505 trial, a randomized, placebo-controlled trial of a prime boost, DNA/rAd5 vaccine consisting of a 6-plasmid DNA vaccine. [15]
- The vaccine induced both cellular and humoral responses. However, these were not associated with protection.[15]
None of the vaccine candidates that have completed efficacy trials to date induced strong bnAb responses. CD8+ T cell responses were induced in STEP, Phambili and HVTN505 studies but were not associated with protection. Only one trial, RV144 demonstrated efficacy and protection was associated with functional binding antibodies. However, efficacy was of suboptimal magnitude and was not durable.
HIV Vaccine
References
- ↑ "NEW U.S. REPORT NAMES VIRUS THAT MAY CAUSE AIDS - The New York Times".
- ↑ Dowdle W (1986). "The search for an AIDS vaccine". Public Health Rep. 101 (3): 232–3. PMC 1477690. PMID 3012619.
- ↑ Fischinger PJ, Robey WG, Koprowski H, Gallo RC, Bolognesi DP (September 1985). "Current status and strategies for vaccines against diseases induced by human T-cell lymphotropic retroviruses (HTLV-I, -II, -III)". Cancer Res. 45 (9 Suppl): 4694s–4699s. PMID 2410115.
- ↑ Wong-Staal F, Shaw GM, Hahn BH, Salahuddin SZ, Popovic M, Markham P, Redfield R, Gallo RC (August 1985). "Genomic diversity of human T-lymphotropic virus type III (HTLV-III)". Science. 229 (4715): 759–62. PMID 2992084.
- ↑ Cheng-Mayer C, Homsy J, Evans LA, Levy JA (April 1988). "Identification of human immunodeficiency virus subtypes with distinct patterns of sensitivity to serum neutralization". Proc. Natl. Acad. Sci. U.S.A. 85 (8): 2815–9. PMC 280090. PMID 3357892.
- ↑ Pitisuttithum P, Gilbert P, Gurwith M, Heyward W, Martin M, van Griensven F, Hu D, Tappero JW, Choopanya K (December 2006). "Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand". J. Infect. Dis. 194 (12): 1661–71. doi:10.1086/508748. PMID 17109337.
- ↑ Flynn NM, Forthal DN, Harro CD, Judson FN, Mayer KH, Para MF (March 2005). "Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection". J. Infect. Dis. 191 (5): 654–65. doi:10.1086/428404. PMID 15688278.
- ↑ Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A, Blanchard J, Irwin CE, Safrit JT, Mittler J, Weinberger L, Kostrikis LG, Zhang L, Perelson AS, Ho DD (March 1999). "Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques". J. Exp. Med. 189 (6): 991–8. PMC 2193038. PMID 10075982.
- ↑ Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ, Ghrayeb J, Forman MA, Montefiori DC, Rieber EP, Letvin NL, Reimann KA (February 1999). "Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes". Science. 283 (5403): 857–60. PMID 9933172.
- ↑ Altfeld M, Kalife ET, Qi Y, Streeck H, Lichterfeld M, Johnston MN, Burgett N, Swartz ME, Yang A, Alter G, Yu XG, Meier A, Rockstroh JK, Allen TM, Jessen H, Rosenberg ES, Carrington M, Walker BD (October 2006). "HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8(+) T Cell Response against HIV-1". PLoS Med. 3 (10): e403. doi:10.1371/journal.pmed.0030403. PMC 1626551. PMID 17076553.
- ↑ Buchbinder SP, Mehrotra DV, Duerr A, Fitzgerald DW, Mogg R, Li D, Gilbert PB, Lama JR, Marmor M, Del Rio C, McElrath MJ, Casimiro DR, Gottesdiener KM, Chodakewitz JA, Corey L, Robertson MN (November 2008). "Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial". Lancet. 372 (9653): 1881–1893. doi:10.1016/S0140-6736(08)61591-3. PMC 2721012. PMID 19012954.
- ↑ Gray GE, Allen M, Moodie Z, Churchyard G, Bekker LG, Nchabeleng M, Mlisana K, Metch B, de Bruyn G, Latka MH, Roux S, Mathebula M, Naicker N, Ducar C, Carter DK, Puren A, Eaton N, McElrath MJ, Robertson M, Corey L, Kublin JG (July 2011). "Safety and efficacy of the HVTN 503/Phambili study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study". Lancet Infect Dis. 11 (7): 507–15. doi:10.1016/S1473-3099(11)70098-6. PMC 3417349. PMID 21570355.
- ↑ Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, Premsri N, Namwat C, de Souza M, Adams E, Benenson M, Gurunathan S, Tartaglia J, McNeil JG, Francis DP, Stablein D, Birx DL, Chunsuttiwat S, Khamboonruang C, Thongcharoen P, Robb ML, Michael NL, Kunasol P, Kim JH (December 2009). "Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand". N. Engl. J. Med. 361 (23): 2209–20. doi:10.1056/NEJMoa0908492. PMID 19843557.
- ↑ Robb ML, Rerks-Ngarm S, Nitayaphan S, Pitisuttithum P, Kaewkungwal J, Kunasol P, Khamboonruang C, Thongcharoen P, Morgan P, Benenson M, Paris RM, Chiu J, Adams E, Francis D, Gurunathan S, Tartaglia J, Gilbert P, Stablein D, Michael NL, Kim JH (July 2012). "Risk behaviour and time as covariates for efficacy of the HIV vaccine regimen ALVAC-HIV (vCP1521) and AIDSVAX B/E: a post-hoc analysis of the Thai phase 3 efficacy trial RV 144". Lancet Infect Dis. 12 (7): 531–7. doi:10.1016/S1473-3099(12)70088-9. PMC 3530398. PMID 22652344.
- ↑ 15.0 15.1 Hammer SM, Sobieszczyk ME, Janes H, Karuna ST, Mulligan MJ, Grove D, Koblin BA, Buchbinder SP, Keefer MC, Tomaras GD, Frahm N, Hural J, Anude C, Graham BS, Enama ME, Adams E, DeJesus E, Novak RM, Frank I, Bentley C, Ramirez S, Fu R, Koup RA, Mascola JR, Nabel GJ, Montefiori DC, Kublin J, McElrath MJ, Corey L, Gilbert PB (November 2013). "Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine". N. Engl. J. Med. 369 (22): 2083–92. doi:10.1056/NEJMoa1310566. PMC 4030634. PMID 24099601.